Contrasting Effects of TGF‐β1 and TNF‐α on the Development of Dendritic Cells from Progenitors in Mouse Bone Marrow

Abstract

Dendritic cells (DC) are a distinct population of leukocytes and specialized antigen-presenting cells for T cell responses. Prior work has shown that GM-CSF can induce the development of large numbers of DC from proliferating progenitors in mouse bone marrow. We have monitored the effects of potentially enhancing and suppressive cytokines in these cultures. In this system, many immature DC develop from proliferating precursors during the first six days of culture, and between days 6-8 maturation of typical nonadherent and nonreplicating DC takes place. The maturation is accompanied by a large increase in the expression of major histocompatibilities complex class II (MHC II) and B7-2/CD86, and in mixed leukocyte reaction stimulating activity. Tumor necrosis factor-α (TNF-α), previously shown to be required for development of human DC, was found to enhance the maturation of mouse DC in the last two days of culture. Transforming growth factor-β1(TGF-β1), on the other hand, almost totally blocked DC maturation, but it had to be given in the first six days of culture when the DC were actively proliferating. TGF-β1 did not block the production of immature, MHC II-positive but B7-2/CD86-negative DC. Maturation would take place between days 6-8 as long as the cultures were depleted of Fc-receptor-bearing cells, or if TNF-α were added. In both instances, maturation was not blocked even when TGF-β1 remained in the culture. We conclude that the development of DC, in response to GM-CSF, can be modified by other cytokines. TGF-β1 is suppressive but only indirectly via Fc-receptorbearing suppressive cells, presumably suppressive macrophages, while TNF-α enhances the final maturation of DC.

Dendritic cells exposed in vitro to TGF-beta1 ameliorate experimental autoimmune myasthenia gravis

“…Strobl and Knapp [28] reported that DC generated in cultures of CD34 + human haemopoietic progenitor cells stimulated with TGF-b1 are arrested in their maturation at an immature differentiation stage and lack specific phenotypic features of mature DC (CD83 -). Yamaguchi et al [16] observed that TGF-b1 addition to GM-CSFsupplemented cultures of murine bone marrow cells increases DC yields and suppresses DC maturation. These effects of TGF-b1 are reversed by addition of anti-TGF-b1 to the cultures.…”

“…We have reported that TGF-b1 ameliorates the development of EAE, accompanied by apoptosis of CD4 + T cells induced by DC-derived NO [14]. TGF-b1 promotes DC development in vitro [15] and suppresses DC maturation [16,17] …”

Adenoviral delivery of CTLA4Ig into myeloid dendritic cells promotes their in vitro tolerogenicity and survival in allogeneic recipients

“…Candidate genes include cytokines and other molecules that undermine the allostimulatory role of DC and include viral (v) IL-10, 42,43 TGF␤, 19,44 Fas L, 23,45 CTLA4Ig, 16,23 CD40Ig and nitric oxide. 18 By using viral vectors to modify DC in vitro, there is in principle reduced administration of viral proteins, in contrast to direct in vivo administration of viral vectors, thus minimizing the generation of antiviral Abs that can prevent repetition of treatment.…”

TGFβ-dependent gene expression profile during maturation of dendritic cells

“…TGFb promotes DC development in vitro 9 but suppresses their final maturation. 10 When modulated by TGFb-expressing adenoviral vectors, DC become tolerogenic and suppress T-cell alloreactivity. 11 Immature DC can lead to peripheral tolerance by inducing differentiation of regulatory T cells.…”